DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed December 30, 2025 is pending.
Claim 27 is canceled.
Claims 1-26 are pending.
Claim 1 is an independent claim.
Applicant’s election without traverse of the species of SIRP
α
D1 domain variant comprising the amino acid sequence of SEQ ID NO: 85, a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, bladder cancer, and pembrolizumab in the reply filed on December 30, 2025 is acknowledged.
Claims 20 and 24 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions.
Claims 1-19, 21-23, 25, and 26 are currently under consideration.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-19, 21-23, 25, and 26 are rejected under 35 U.S.C. 103 as being unpatentable Kauder et al. 2018 (PLoS ONE. 13(8): e0201832. 1-33) as evidenced by post-filing art Evorpacept (GtoPdb Ligand ID: 11592, ALX148) (n.d.) IUPHAR Guide to Immunopharmacology (https://www.guidetoimmunopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=11592) or Pons et al. 2020 (U.S. Patent No. 10,696,730, an IDS reference filed 10/15/2024) in view of Maas et al. 2021 (Expert Opin. Biol. Ther. 21(7), 801-809)
In view of the Applicant’s species election filed 12/30/2025, independent claim 1 is drawn to a method of treating urothelial cancer in an individual, comprising administering to the individual (a) an effective amount of a fusion polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, and (b) an effective amount of enfortumab vedotin, wherein the SIRPα D1 domain variant of the fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 85; and wherein the Fc domain variant of the fusion polypeptide is (i) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat.
Dependent claim 2 limits the urothelial cancer to locally advanced urothelial cancer or metastatic urothelial cancer.
Dependent claim 3 limits the urothelial cancer to bladder cancer.
Dependent claims 4-6 limit the individual to an individual who has received prior treatment with an immune checkpoint inhibitor (CPI). Claims 5 and 6 limit the CPI to a PD-1 inhibitor and pembrolizumab, respectively.
Claim 7 limits the individual to an individual who has received prior treatment with a platinum-containing chemotherapy.
Claim 8 limits the individual to an individual who has had progression or recurrence of urothelial cancer during or following receipt of most recent prior therapy.
Claim 9 limits the individual to an individual who has not received prior treatment with a monomethylauristatin (MMAE)-based antibody-drug conjugate.
Claim 10 limits the individual to an individual who has not received prior treatment with enfortumab vedotin.
Claim 11 limits the individual to an individual who has not received prior treatment with a therapeutic agent that blocks the interaction between CD47 and SIRPα-li.
Claim 12 recites that the enfortumab vedotin is administered to the individual in one or more 28-day cycles, and wherein the enfortumab vedotin is administered to the individual at a dose of 1.25 mg/kg IV on Days 1, 8 and 15 of each 28- day cycle.
Claim 13 recites that the enfortumab vedotin is administered intravenously.
Claims 14-17 recite that the fusion polypeptide is administered to the individual at a dose up to about 60 mg/kg. Claim 15 also recites that the fusion polypeptide is administered to the individual at a dose of about 30 mg/kg once every two weeks (q2w). Claim 16 also recites that the fusion polypeptide is administered to the individual at a dose of about 20 mg/kg once every two weeks (q2w). Claim 17 also recites that the fusion polypeptide is administered to the individual at a dose of about 15 mg/kg once every two weeks (q2w).
Claim 18 recite that the fusion polypeptide is administered intravenously.
Claim 22 recite that Fc domain variant comprises the amino acid sequence of SEQ ID NO: 91.
Claim 23 recites that the fusion polypeptide comprises SEQ ID NO: 136.
Claim 25 recites that the fusion polypeptide forms a homodimer.
Claim 26 limits the individuals to a human.
Regarding claims 1, 19, 21-23, and 26, Kauder et al. teach methods of treating mice comprising human tumor xenografts (B-cell lymphoma and gastroesophageal cancer models) with ALX148 in combination with an anti-tumor antibody (e.g. see paragraph spanning pages 14-16 and Fig. 4). ALX148, also known as Evorpacept, is a CD47-blocking molecule that was generated by fusing a modified SIRPα D1 domain (i.e. instant SEQ ID NO: 85) to an inactive human IgG1 Fc (e.g. see Abstract). It is noted that the amino acid sequence of ALX148 comprises instant SEQ ID NO: 85 and an inactive human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations as evidence by post-filing art Evorpacept (GtoPdb Ligand ID: 11592, ALX148) (n.d.) IUPHAR Guide to Immunopharmacology (https://www.guidetoimmunopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=11592). Specifically regarding claims 22 and 3, it is further noted that the inactive human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations of ALX148 is identical to instant SEQ ID NO: 91. The amino acid sequence of ALX148 is identical to instant SEQ ID NOs: 136. See sequence alignments below.
Regarding claim 25, Kauder et al. also teach that ALX148 is a disulfide-linked homodimer (e.g. see page 11, fourth paragraph; and Figure 1A). Kauder et al. also teach that the SIRPα D1 portion of ALX148 contains amino acid substitutions previously shown to dramatically increase affinity for CD47, thus enabling the blockade of wild-type SIRPα binding (e.g. see page 3, second paragraph). The Fc portion of ALX148 confers increased molecular mass and interaction with the neonatal Fc receptor for SIRPα D1, both of which are associated with extended pharmacokinetics (e.g. see page 3, third paragraph). In ALX148, the Fc domain has a unique set of amino acid substitutions designed to eliminate binding to human Fcγ receptors and complement C1q protein. This absence of effector function is meant to prevent ALX148 from engaging Fcγ receptors and targeting normal cells for phagocytosis, differentiating ALX148 from other CD47-blocking molecules that have active Fc domains (e.g. see page 3, third paragraph).
Kauder et al. also teach that CD47 is a widely expressed cell surface protein that functions as an immune checkpoint in cancer (e.g. see Abstract). When expressed by tumor cells, CD47 can bind SIRPα on myeloid cells, leading to suppression of tumor cell phagocytosis and other innate immune functions. CD47-SIRPα signaling has also been implicated in the suppression of adaptive antitumor responses. Therapeutic blockade of the CD47 pathway may stimulate antitumor immunity and improve cancer therapy (e.g. see Abstract).
Kauder et al. also teach that as an additional immune checkpoint, the CD47-SIRPα axis acts upon innate immunity by suppressing myeloid cell function (e.g. see page 25, second paragraph). ALX148 blocks the CD47-SIRPα interaction and induces antitumor immunity by bridging innate and adaptive immune responses while maintaining a favorable preclinical safety profile (e.g. see page 25, second paragraph).
Kauder et al. further teach that while ALX148 does not itself possess an active Fc domain, it enhances the activity of combination antitumor antibodies (e.g. see page 26, second paragraph). For example, ALX148 enhanced the antitumor activity of obinutuzumab, trastuzumab, and rituximab in murine xenograft models of tumorigenesis using human cancer cell lines. These results demonstrate that ALX148 enhances the antitumor efficacy of myeloid cells in vivo. Ultimately, Kauder et al. teach that ALX148 can be used in combination with a wide range of anti-cancer antibodies (e.g. see page 26, second paragraph).
Regarding claims 14-17, Kauder et al. also teach a comparison of CD47 occupancy at 10 and 30 mg/kg 30 mg/kg demonstrated that greater levels of ALX148 are required to attain full occupancy in the tumor than are required for the periphery (e.g. see page 28, first paragraph). Importantly, these effects were observed at well-tolerated doses of ALX148 (e.g. see page 28, first paragraph).
Regarding claims 15-17 and 26, the pharmacokinetic and pharmacodynamic properties of ALX148 are consistent with that of an anti-CD47 antibody observed in NHP and support a weekly or biweekly dosing frequency in human patients (e.g. see page 28, second paragraph).
Regarding claim 18, Kauder et al. also teach the intravenous administration of ALX148 (e.g. see page 9, third paragraph; and Figure 2).
In summary, Kauder et al. teach that ALX148 induces innate and adaptive immune responses, enhances preclinical anti-tumor activity in combination with a variety of cancer therapies, and has a favorable preclinical safety profile (e.g. see page 28, third paragraph).
Sequence alignment of ALX148 (Qy) and instant SEQ ID NO: 85 and wildtype human IgG1 Fc (Db). Instant SEQ ID NO: 85 underlined and the L234A, L235A, G237A, and N297A point mutations are bolded and italicized:
Query Match 98.9%; Score 1824; DB 1; Length 345;
Best Local Similarity 98.8%;
Matches 341; Conservative 0; Mismatches 4; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
Qy 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
|||||||||||| | ||||||||||||||||||||||||||||||||||||||||||||
Db 121 KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
Qy 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||
Db 181 VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
Qy 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
Qy 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
|||||||||||||||||||||||||||||||||||||||||||||
Db 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
Sequence alignment of ALX148 (Qy) and instant SEQ ID NO: 91 (Db):
Query Match 66.4%; Score 1224; DB 1; Length 226;
Best Local Similarity 100.0%;
Matches 226; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 120 DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 179
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 60
Qy 180 GVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 239
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 120
Qy 240 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 299
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 180
Qy 300 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 226
Sequence alignment of ALX148 (Qy) and instant SEQ ID NO: 136 (Db):
Query Match 100.0%; Score 1844; DB 1; Length 345;
Best Local Similarity 100.0%;
Matches 345; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
Qy 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
Qy 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
Qy 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
Qy 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
|||||||||||||||||||||||||||||||||||||||||||||
Db 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
Regarding claims 1, 19, and 21-23, Pons et al. method of treating an individual having cancer, the method comprising administering to the individual: (1) a pharmaceutical composition comprising a dimer and a pharmaceutically acceptable excipient, wherein the dimer comprises a polypeptide that comprises: (a) a signal-regulatory protein α (SIRP-α) D1 variant comprising SEQ ID NO: 85; and (b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index, wherein the C-terminus of the SIRP-α D1 variant is linked to the N-terminus of the human IgG1 Fc region; and (2) at least one additional agent to the individual, wherein the at least one additional agent is an antibody (e.g. see claim 13).
Pons et al. also teach that high affinity SIRP-α constructs, such as SEQ ID NO: 104, can effectively attenuate tumor growth and synergize with rituximab in an in vivo mouse model of cancer (e.g. see column 141, line 53 – column 42, line 19).
It is noted that SEQ ID NO: 85 is identical to instant SEQ ID NO: 85 and SEQ ID NO: 104 is identical to instant SEQ ID NO: 136 which comprises instant SEQ ID NOs: 85 and 91. Instant SEQ ID NO: 91 is the human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations. See sequence alignments below.
Regarding claims 14-17, Pons et al. teach a dosage of a polypeptide of the disclosure ranging from about 0.1 to about 50 mg/kg and that the dosage can be adapted by a physician in accordance with the extent of the disease and different parameters of the subject (e.g. see column 100, lines 25-35). Pons et al. also teach that NSG mice are treated with 10 mg/kg of SEQ ID NO: 104 (e.g. see column 141, lines 22-28).
Regarding claim 18, Pons et al. teach the intravenous administration of SEQ ID NO: 104 (e.g. see column 129, lines 21-38).
Regarding claim 25, Pons et al. teach a homodimer SIRP-α Fc fusion of SEQ ID NO: 136 (e.g. see column 136, lines 64 and 65; and Figure 5B). It is noted that Pons et al.’s SEQ ID NO: 136 is also identical to instant SEQ ID NO: 136 which comprises instant SEQ ID NOs: 85 and 91, wherein instant SEQ ID NO: 91 is the human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations. See sequence alignments below.
Regarding claim 26, Pons et al. teach a method of treating mice comprising human tumor xenografts with SEQ ID NO: 104 (e.g. see column 141, lines 6-31).
Sequence alignment of Pons et al. SEQ ID NO: 85 (Qy) and instant SEQ ID NO: 85 (Db):
Query Match 100.0%; Score 620; DB 1; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS 119
Sequence alignment of Pons et al. SEQ ID NO: 104 (Qy) and instant SEQ ID NO: 136 (Db). Instant SEQ ID NO: 85 underlined and SEQ ID NO: 91 is bolded and italicized with the L234A, L235A, G237A, and N297A point mutations underlined:
Query Match 100.0%; Score 1844; DB 1; Length 346;
Best Local Similarity 100.0%;
Matches 345; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
Qy 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
Qy 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
Qy 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
Qy 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
|||||||||||||||||||||||||||||||||||||||||||||
Db 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
Sequence alignment of Pons et al. SEQ ID NO: 136 (Qy) and instant SEQ ID NO: 136 (Db). Instant SEQ ID NO: 85 underlined and SEQ ID NO: 91 is bolded and italicized with the L234A, L235A, G237A, and N297A point mutations underlined:
Query Match 100.0%; Score 1844; DB 1; Length 345;
Best Local Similarity 100.0%;
Matches 345; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
Qy 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
Qy 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
Qy 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
Qy 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
|||||||||||||||||||||||||||||||||||||||||||||
Db 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
Kauder et al. and Pons et al. do not teach that the cancer is urothelial cancer or that the combination anti-cancer antibody is enfortumab vedotin.
Maas et al. teach that bladder cancer, a type of urothelial cancer (UC), is the fourth most common cancer in men and the 11th most common when both sexes are considered (e.g. see page 801, left column, first paragraph). For advanced or metastatic bladder cancer, various systemic therapies are currently available ranging from chemotherapy and immunotherapy to targeted therapies (e.g. see page 801, left column, third paragraph). Despite the increasing importance of the immune checkpoint inhibitors (ICI), e.g. atezolizumab, pembrolizumab, or nivolumab, the backbone of UC treatment is still a platinum-based chemotherapy in the first-line setting (e.g. see page 801, left column, third paragraph).
Regarding claims 1-3, as an alternative to platinum-based chemotherapy, Maas et al. teach enfortumab vedotin (EV), the first representative of the new class of antibody-drug conjugates (ADCs) for patients with advanced and metastatic urothelial carcinoma (e.g. see page 807, right column, first paragraph). EV comprises monomethyl auristatin E (MMAE) conjugated to an anti-nectin-4 antibody (e.g. see page 802, right column, fourth paragraph). Nectin-4 is highly expressed in urothelial cancer and MMAE, a highly toxic small molecule therapeutic agent, inhibits mitosis by blocking the polymerization of tubulin (e.g. see page 802, right column, fourth paragraph and page 807, right column, first paragraph).
Regarding claims 4-11, Maas et al. also teach that there is a high unmet need for new agents in order to expand the first-line, the platinum-refractory, and the post-ICI space in metastatic urothelial cancer (mUC) treatment (e.g. see page 802, right column, third paragraph). Furthermore, an increase in objective response rates, PFS, and OS is warranted, either by new agents alone or in combination with ICI or chemotherapy. This medical need could be addressed by EV as early data shows promising results (e.g. see page 802, right column, third paragraph). For example, Maas et al. teach that EV has an encouraging overall response rate (ORR) in Phase I and II studies and has favorable tolerability (e.g. see page 807, right column, first paragraph).
Further regarding claim 1, Maas et al. further teach that combination therapies of EV with immunotherapies and cytotoxic chemotherapies are encouraging and provide an excellent treatment option for patients (e.g. see page 108, left column, first paragraph). Moreover, Maas et al. teach that synergistic effects by the combination of ICI and EV can be expected as both drugs use different modes of action (e.g. see page 108, left column, first paragraph).
Regarding claims 12 and 13, Maas et al. also teach a dosing schedule of EV as 1.25 mg/kg body weight of EV administered intravenously on days 1, 8, and 15 of a 28-day cycle (e.g. see page 803, left column, fourth paragraph; page 803, right column, first paragraph; and box 1, drug summary box).
Regarding claim 26, Maas et al. teach several clinical trials using EV to treat UC in humans (e.g. see Table 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Kauder et al. or Pons et al. to incorporate the teachings of Maas et al. to include that the cancer is urothelial cancer or that the combination anti-cancer antibody is enfortumab vedotin. This is because combination therapies of EV with immunotherapies and cytotoxic chemotherapies, such as Kauder et al.’s ALX148 or Pons et al.’s fusion polypeptide, are encouraging and provide an excellent treatment option for patients with UC (Maas et al.).
Bladder cancer, a type of UC, is very common and there is a high unmet need for new therapies (either alone or in combination with ICI or chemotherapy) to expand the first-line, the platinum-refractory, and the post-ICI space in mUC treatment (Maas et al.). This medical need could be addressed by EV given its encouraging ORR and favorable tolerability (Maas et al.).
Regarding Kauder et al., ALX148, also known as Evorpacept, is a CD47-blocking molecule that was generated by fusing a modified SIRPα D1 domain (i.e. instant SEQ ID NO: 85) to an inactive human IgG1 Fc comprising L234A, L235A, G237A, and N297A mutations (Kauder et al). CD47 is a widely expressed cell surface protein that functions as an immune checkpoint in cancer (Kauder et al). ALX148 blocks the CD47-SIRPα interaction and induces antitumor immunity by bridging innate and adaptive immune responses while maintaining a favorable preclinical safety profile (Kauder et al).
Regarding Pons et al., high affinity SIRP-α constructs can effectively attenuate tumor growth and synergize with rituximab, an anti-CD20 antibody, in vivo (Pons et al.).
Given that bladder cancer, a type of UC, is so common (Maas et al.), combination therapies of EV with immunotherapies and cytotoxic chemotherapies are encouraging and provide an excellent treatment option for patients with UC (Maas et al.), ALX148, an ICI, enhances anti-tumor activity in combination with a variety of cancer therapies (Kauder et al.), and high affinity SIRP-α constructs can effectively attenuate tumor growth and synergize with anti-cancer antibodies in vivo; it would have been obvious to a skilled artisan, with the goal of improving the anti-cancer activity of EV for treating advanced or metastatic UC, to modify the method of treating cancer with ALX148 in combination with an anti-tumor antibody as taught by Kauder et al. or the method treating an individual having cancer with the SIRP-α D1-Fc variant fusion polypeptide in combination with an antibody as taught by Pons et al., to specifically treat advanced or metastatic UC, including bladder cancer, with the combination anti-cancer ADC EV with a reasonable expectation of success.
Kauder et al. teach that ALX148 can be used in combination with a wide range of anti-cancer antibodies and Pons et al. teach that their SIRP-α D1-Fc variant fusion polypeptide is used in combination with an antibody, including an anti-cancer antibody, such as Maas et al.’s EV. ALX148 and Pons et al.’s SIRP-α D1-Fc variant fusion polypeptide would be expected to reduce any suppressed tumor cell phagocytosis or other innate or adaptive immune functions caused by the CD47-SIRPα signaling axis that may hinder EV treatment of UC.
It is also noted that regarding claims 12-18 drawn to the dosing of EV and the fusion polypeptide, determination of the optimal intervals of treatment and the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made and lends no patentable import to the claimed invention. The duration of treatment, the effective dosages and like factors are well within the knowledge and expertise of the medical practitioner.
It would have been obvious to one of ordinary skill in the art at the time Applicants' invention was filed to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between Applicant’s claimed method and that suggested by the teachings of the prior art, the differences would be appear minor in nature. Although the prior art do not teach all the various permutations of interval ranges as claimed in claims 12-18, it would be conventional and within the skill of the art to identify the optional intervals of treatment. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP §§ 2144.05 part II A.
Regarding claim 26, while neither Kauder et al. or Pons et al. specifically teach treating a human, both references teach methods of treating mice comprising xenografts of human tumors. It is well known that mice comprising xenografts of human tumors are meant to model treatment in humans. Therefore, been it would have been obvious to a skilled artisan to use the combination therapy taught by Kauder et al. or Pons et al. in view of Maas et al. in a human specifically.
Nonetheless, Maas et al. teach several clinical trials using EV to treat UC in humans thereby providing further rationale for a combination therapy of EV and the SIRP-α D1-Fc variant fusion polypeptide for treating UC in humans.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-19, 21-23, 25, and 26 are rejected on the ground of nonstatutory double patenting (NSDP) as being unpatentable over claims 1-27 of U.S. Patent No. 10,696,730 (the ‘730 Patent, an IDS reference filed 10/15/2024) in view Kauder et al. 2018 (PLoS ONE. 13(8): e0201832. 1-33) as evidenced by post-filing art Evorpacept (GtoPdb Ligand ID: 11592, ALX148) (n.d.) IUPHAR Guide to Immunopharmacology (https://www.guidetoimmunopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=11592) or Pons et al. 2020 (U.S. Patent No. 10,696,730, an IDS reference filed 10/15/2024) and of Maas et al. 2021 (Expert Opin. Biol. Ther. 21(7), 801-809).
The instant claims are drawn to a method of treating urothelial cancer in an individual, comprising administering to the individual (a) an effective amount of a fusion polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, and (b) an effective amount of enfortumab vedotin, wherein the SIRPα D1 domain variant of the fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 85; and wherein the Fc domain variant of the fusion polypeptide is (i) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat
The claims in the ‘730 Patent are drawn to a polypeptide, comprising: (a) a signal-regulatory protein α (SIRP-α) D1 variant comprising SEQ ID NO: 85; and (b) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations; nucleic acids; vectors; host cells; methods of producing a polypeptide; pharmaceutical compositions; methods of treating an individual having cancer; and a dimer.
It is noted that SEQ ID NO: 85 is identical to instant SEQ ID NO: 85 and SEQ ID NO: 136 is identical to instant SEQ ID NO: 136 which comprises instant SEQ ID NOs: 85 and 91. Instant SEQ ID NO: 91 is the human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations. See sequence alignments below.
Sequence alignment of Pons et al. SEQ ID NO: 85 (Qy) and instant SEQ ID NO: 85 (Db):
Query Match 100.0%; Score 620; DB 1; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS 119
Sequence alignment of Pons et al. SEQ ID NO: 136 (Qy) and instant SEQ ID NO: 136 (Db). Instant SEQ ID NO: 85 underlined and SEQ ID NO: 91 is bolded and italicized with the L234A, L235A, G237A, and N297A point mutations underlined:
Query Match 100.0%; Score 1844; DB 1; Length 345;
Best Local Similarity 100.0%;
Matches 345; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
Qy 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
Qy 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
Qy 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
Qy 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
|||||||||||||||||||||||||||||||||||||||||||||
Db 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
The claims in the ‘730 Patent differ from the instant invention by not reciting a method of treating urothelial cancer with a combination of the SIRP-α D1-Fc variant fusion polypeptide and enfortumab vedotin.
The teachings of Kauder et al., Pons et al, and Maas et al. are outlined in the 103 rejection above. It is noted that the ‘730 Patent’s SEQ ID NO: 136 is identical to Kauder et al.’s ALX148 and Pons et al.’s SEQ ID NOs: 104 and 136. See the 103 rejection above.
It would be obvious to one of ordinary skill in the art modify the ‘730 Patent to incorporate the teachings of Kauder et al. or Pons et al. and Maas et al. to include a method of treating urothelial cancer with a combination of the SIRP-α D1-Fc variant fusion polypeptide and enfortumab vedotin. This is because combination therapies of EV with immunotherapies and cytotoxic chemotherapies, such as Kauder et al.’s ALX148 or Pons et al.’s fusion polypeptide, are encouraging and provide an excellent treatment option for patients with UC (Maas et al.).
Bladder cancer, a type of UC, is very common and there is a high unmet need for new therapies (either alone or in combination with ICI or chemotherapy) to expand the first-line, the platinum-refractory, and the post-ICI space in mUC treatment (Maas et al.). This medical need could be addressed by EV given its encouraging ORR and favorable tolerability (Maas et al.).
Regarding Kauder et al., ALX148, also known as Evorpacept, is a CD47-blocking molecule that was generated by fusing a modified SIRPα D1 domain (i.e. instant SEQ ID NO: 85) to an inactive human IgG1 Fc comprising L234A, L235A, G237A, and N297A mutations (Kauder et al). CD47 is a widely expressed cell surface protein that functions as an immune checkpoint in cancer (Kauder et al). ALX148 blocks the CD47-SIRPα interaction and induces antitumor immunity by bridging innate and adaptive immune responses while maintaining a favorable preclinical safety profile (Kauder et al).
Regarding Pons et al., high affinity SIRP-α constructs can effectively attenuate tumor growth and synergize with rituximab, an anti-CD20 antibody, in vivo (Pons et al.).
Given that bladder cancer, a type of UC, is so common (Maas et al.), combination therapies of EV with immunotherapies and cytotoxic chemotherapies are encouraging and provide an excellent treatment option for patients with UC (Maas et al.), ALX148, an ICI, enhances anti-tumor activity in combination with a variety of cancer therapies (Kauder et al.), and high affinity SIRP-α constructs can effectively attenuate tumor growth and synergize with anti-cancer antibodies in vivo (Pons et al.); it would be obvious to a skilled artisan, with the goal of improving the anti-cancer activity of EV for treating advanced or metastatic UC, to include the ‘730 Patent’s SIRP-α D1-Fc variant fusion polypeptide in a method of treating urothelial cancer or to modify the ‘730 Patent’s method of treating cancer for a method of treating urothelial cancer, including bladder cancer, with a combination of the SIRP-α D1-Fc variant fusion polypeptide and enfortumab vedotin with a reasonable expectation of success.
Kauder et al. teach that ALX148 can be used in combination with a wide range of anti-cancer antibodies and Pons et al. teach that their SIRP-α D1-Fc variant fusion polypeptide is used in combination with an antibody, including an anti-cancer antibody, such as Maas et al.’s EV. ALX148 and Pons et al.’s SIRP-α D1-Fc variant fusion polypeptide, which are identical to the ‘730 Patent’s SIRP-α D1-Fc variant fusion polypeptide, would be expected to reduce any suppressed tumor cell phagocytosis or other innate or adaptive immune functions caused by the CD47-SIRPα signaling axis that may hinder EV treatment of UC.
It is also noted that regarding claims 12-18 drawn to the dosing of EV and the fusion polypeptide, determination of the optimal intervals of treatment and the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made and lends no patentable import to the claimed invention. The duration of treatment, the effective dosages and like factors are well within the knowledge and expertise of the medical practitioner.
It would be obvious to one of ordinary skill in the art at the time Applicants' invention was filed to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between Applicant’s claimed method and that suggested by the teachings of the prior art, the differences would be appear minor in nature. Although the prior art do not teach all the various permutations of interval ranges as claimed in claims 12-18, it would be conventional and within the skill of the art to identify the optional intervals of treatment. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP §§ 2144.05 part II A.
Regarding claim 26, while neither Kauder et al. or Pons et al. specifically teach treating a human, both references teach methods of treating mice comprising xenografts of human tumors. It is well known that mice comprising xenografts of human tumors are meant to model treatment in humans. Therefore, been it would have been obvious to a skilled artisan to use the combination therapy taught by the ‘730 Patent in view Kauder et al. or Pons et al. and Maas et al. in a human specifically.
Nonetheless, Maas et al. teach several clinical trials using EV to treat UC in humans thereby providing further rationale for a combination therapy of EV and the SIRP-α D1-Fc variant fusion polypeptide for treating UC in humans.
It is further noted that obtaining cDNA / nucleic acids from protein sequences has been routine and conventional in the art and used to make proteins of interest, including polypeptides of interest. For example, expression vectors can comprise polynucleotides sequences encoding amino acids, in turn polypeptides (e.g., polypeptides comprising instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations). Given that obtaining cDNA / nucleic acids from protein sequence sequences is routine and conventional, It would be obvious to the ordinary artisan to obtaining cDNA to produce proteins of interest.
This applies to the instant case where it would be obvious to a skilled artisan to obtain the isolated nucleic acid and the vector of the instant invention from the polypeptide constructs of the ‘730 Patent.
As such, the claims in the ‘730 Patent would render the instant claims obvious.
Claims 1-19, 21-23, 25, and 26 are (provisionally) rejected on the ground of nonstatutory double patenting (NSDP) as being unpatentable over the claims in the following U.S. Patents and Applications in view Kauder et al. 2018 (PLoS ONE. 13(8): e0201832. 1-33) as evidenced by post-filing art Evorpacept (GtoPdb Ligand ID: 11592, ALX148) (n.d.) IUPHAR Guide to Immunopharmacology (https://www.guidetoimmunopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=11592) or Pons et al. 2020 (U.S. Patent No. 10,696,730, an IDS reference filed 10/15/2024) and of Maas et al. 2021 (Expert Opin. Biol. Ther. 21(7), 801-809) for similar reasons to the ‘730 Patent above.
The instant claims are drawn to a method of treating urothelial cancer in an individual, comprising administering to the individual (a) an effective amount of a fusion polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, and (b) an effective amount of enfortumab vedotin, wherein the SIRPα D1 domain variant of the fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 85; and wherein the Fc domain variant of the fusion polypeptide is (i) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat
Claims 165-179 of U.S. Application No. 18/540,092 (the ‘092 Application) are drawn to a method of treating an individual having non-Hodgkin lymphoma, the method comprising administering to the individual:(a) a therapeutically effective amount of a polypeptide that comprises:(i) a signal-regulatory protein a (SIRP-a) D1 variant comprising SEQ ID NO: 85;and (ii) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index, and wherein the C-terminus of the SIRP-aD1 variant is linked to the N-terminus of the human IgG1 Fc region; and(b) an anti-CD20 antibody.
It is noted that SEQ ID NOs: 85, 91, 136 are identical to instant SEQ ID NOs: 85, 91, 136.
Claims 7 and 10 of U.S. Patent No. 12,527,838 (the ‘838 Patent) are drawn to a method of treating cancer in an individual, comprising administering to the individual an effective amount of: (a) a polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, (b) trastuzumab, (c) ramucirumab, and (d) paclitaxel; wherein the SIRPα D1 domain variant comprises the amino acid sequence of SEQ ID NO: 85; wherein the Fc domain variant is a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat; wherein the cancer is gastric cancer or gastroesophageal junction (GEJ) cancer, and wherein the individual has received at least one prior therapy for the gastric or the GEJ cancer.
It is noted that SEQ ID NOs: 85 and 136 are identical to instant SEQ ID NOs: 85 and 136.
Claims 1-7 of U.S. Patent No. 11,613,564 (the ‘564 Patent) are drawn to a method of treating head and neck squamous cell carcinoma (HNSCC) in an individual, comprising administering to the individual an effective amount of (a) a polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, and (b) pembrolizumab, wherein the SIRPα D1 domain variant comprises the amino acid sequence of SEQ ID NO: 85; wherein the Fc domain variant is a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat; and wherein the HNSCC in the individual has progressed during a prior platinum therapy or after the prior platinum therapy; wherein the individual has not received prior therapy with an immune checkpoint inhibitor; and wherein the individual is a human.
It is noted that SEQ ID NOs: 85, 91, 136 are identical to instant SEQ ID NOs: 85, 91, 136.
Claims 25 and 29 of U.S. Application No. 19/084,515 (the ‘515 Application) are drawn to a method of treating HER2-positive cancer in an individual, comprising administering to the individual an effective amount of (a) a polypeptide comprising a SIRPaD1 domain variant and an Fc domain variant, and (b) an anti-HER2 antibody, wherein the SIRPaD1 domain variant comprises the amino acid sequence of SEQ ID NO: 85; wherein the Fc domain variant is (i) a human IgGI Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat;(ii) a human IgG2 Fc region comprising A330S, P331S, and N297A mutations, wherein numbering is according to the EU index of Kabat;(iii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, anddelG236 mutations, wherein numbering is according to the EU index of Kabat; or (iv) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, delG236, and N297A mutations, wherein numbering is according to the EU index of Kabat; and wherein the cancer in the individual has progressed following a prior treatment with a fluoropyrimidine-based therapy and/or a prior treatment with an anti-HER2 antibody, and wherein the individual is a human.
It is noted that SEQ ID NOs: 85 and 136 are identical to instant SEQ ID NOs: 85 and 136.
The claims in the above Patents and Applications differ from the instant invention by not reciting a method of treating urothelial cancer with a combination of the SIRP-α D1-Fc variant fusion polypeptide and enfortumab vedotin.
The teachings of Kauder et al., Pons et al, and Maas et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art modify the above Patents and Applications to incorporate the teachings of Kauder et al. or Pons et al. and Maas et al. to include a method of treating urothelial cancer with a combination of the SIRP-α D1-Fc variant fusion polypeptide and enfortumab vedotin. This is because combination therapies of EV with immunotherapies and cytotoxic chemotherapies, such as Kauder et al.’s ALX148 or Pons et al.’s fusion polypeptide, are encouraging and provide an excellent treatment option for patients with UC (Maas et al.).
Bladder cancer, a type of UC, is very common and there is a high unmet need for new therapies (either alone or in combination with ICI or chemotherapy) to expand the first-line, the platinum-refractory, and the post-ICI space in mUC treatment (Maas et al.). This medical need could be addressed by EV given its encouraging ORR and favorable tolerability (Maas et al.).
Regarding Kauder et al., ALX148, also known as Evorpacept, is a CD47-blocking molecule that was generated by fusing a modified SIRPα D1 domain (i.e. instant SEQ ID NO: 85) to an inactive human IgG1 Fc comprising L234A, L235A, G237A, and N297A mutations (Kauder et al). CD47 is a widely expressed cell surface protein that functions as an immune checkpoint in cancer (Kauder et al). ALX148 blocks the CD47-SIRPα interaction and induces antitumor immunity by bridging innate and adaptive immune responses while maintaining a favorable preclinical safety profile (Kauder et al).
Regarding Pons et al., high affinity SIRP-α constructs can effectively attenuate tumor growth and synergize with rituximab, an anti-CD20 antibody, in vivo (Pons et al.).
Given that bladder cancer, a type of UC, is so common (Maas et al.), combination therapies of EV with immunotherapies and cytotoxic chemotherapies are encouraging and provide an excellent treatment option for patients with UC (Maas et al.), ALX148, an ICI, enhances anti-tumor activity in combination with a variety of cancer therapies (Kauder et al.), and high affinity SIRP-α constructs can effectively attenuate tumor growth and synergize with anti-cancer antibodies in vivo (Pons et al.); it would be obvious to a skilled artisan, with the goal of treating bladder cancer and improving the anti-cancer activity of EV, to modify the above Patents and Applications’ method of treating cancer for a method of treating urothelial cancer, including bladder cancer, with a combination of the SIRP-α D1-Fc variant fusion polypeptide and enfortumab vedotin with a reasonable expectation of success.
Kauder et al. teach that ALX148 can be used in combination with a wide range of anti-cancer antibodies and Pons et al. teach that their SIRP-α D1-Fc variant fusion polypeptide is used in combination with an antibody, including an anti-cancer antibody, such as Maas et al.’s EV. ALX148 and Pons et al.’s SIRP-α D1-Fc variant fusion polypeptide, which are identical to the Patents and Applications’ SIRP-α D1-Fc variant fusion polypeptide, would be expected to reduce any suppressed tumor cell phagocytosis or other innate or adaptive immune functions caused by the CD47-SIRPα signaling axis that may hinder EV treatment of UC.
It is also noted that regarding claims 12-18 drawn to the dosing of EV and the fusion polypeptide, determination of the optimal intervals of treatment and the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made and lends no patentable import to the claimed invention. The duration of treatment, the effective dosages and like factors are well within the knowledge and expertise of the medical practitioner.
It would be obvious to one of ordinary skill in the art at the time Applicants' invention was filed to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between Applicant’s claimed method and that suggested by the teachings of the prior art, the differences would be appear minor in nature. Although the prior art do not teach all the various permutations of interval ranges as claimed in claims 12-18, it would be conventional and within the skill of the art to identify the optional intervals of treatment. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP §§ 2144.05 part II A.
Regarding claim 26, while neither Kauder et al. or Pons et al. specifically teach treating a human, both references teach methods of treating mice comprising xenografts of human tumors. It is well known that mice comprising xenografts of human tumors are meant to model treatment in humans. Therefore, been it would have been obvious to a skilled artisan to use the combination therapy taught by the above Patents and Applications in view Kauder et al. or Pons et al. and Maas et al. in a human specifically.
Nonetheless, Maas et al. teach several clinical trials using EV to treat UC in humans thereby providing further rationale for a combination therapy of EV and the SIRP-α D1-Fc variant fusion polypeptide for treating UC in humans.
It is further noted that obtaining cDNA / nucleic acids from protein sequences has been routine and conventional in the art and used to make proteins of interest, including polypeptides of interest. For example, expression vectors can comprise polynucleotides sequences encoding amino acids, in turn polypeptides (e.g., polypeptides comprising instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations). Given that obtaining cDNA / nucleic acids from protein sequence sequences is routine and conventional, It would be obvious to the ordinary artisan to obtaining cDNA to produce proteins of interest.
This applies to the instant case where it would be obvious to a skilled artisan to obtain the isolated nucleic acid and the vector of the instant invention from the polypeptide constructs of the above Patents and Applications.
As such, the claims in the above Patents and Applications would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection for the co-pending Applications since those claims are in fact not patented (i.e. Applications 18/540,092 and 19/084,515)
Claims 1-19, 21-23, 25, and 26 are rejected on the ground of nonstatutory double patenting (NSDP) as being unpatentable over claims 1-36, 44-48, 50-54, 56, 59-117, 120, 126, and 134 of U.S. Patent No. 10,259,859 (the ‘859 Patent, an IDS reference filed 10/15/2024) in view of Kauder et al. 2018 (PLoS ONE. 13(8): e0201832. 1-33) as evidenced by post-filing art Evorpacept (GtoPdb Ligand ID: 11592, ALX148) (n.d.) IUPHAR Guide to Immunopharmacology (https://www.guidetoimmunopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=11592) or Pons et al. 2020 (U.S. Patent No. 10,696,730, an IDS reference filed 10/15/2024) and Maas et al. 2021 (Expert Opin. Biol. Ther. 21(7), 801-809).
The instant claims are drawn to a method of treating urothelial cancer in an individual, comprising administering to the individual (a) an effective amount of a fusion polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, and (b) an effective amount of enfortumab vedotin, wherein the SIRPα D1 domain variant of the fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 85; and wherein the Fc domain variant of the fusion polypeptide is (i) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat
The claims in the ‘859 Patent are drawn to polypeptides, comprising one of a variety of signal-regulatory protein α (SIRP-α) D1 variants; polypeptides, comprising one of a variety of signal-regulatory protein α (SIRP-α) D1 variants and an Fc variant; method of treating an individual having a disease or disorder; an isolated nucleic acid; a vector; a host cell; a method of producing a polypeptide; a pharmaceutical composition; and a composition.
It is noted that SEQ ID NOs: 85, 91, and 104 of the ‘859 Patent are identical to instant SEQ ID NOs: 85, 91, and 136, respectively. SEQ ID NO: 85 is a SIRP-α D1 variant, SEQ ID NO: 91 is a human IgG1 Fc region variant comprising L234A, L235A, G237A, and N297A mutations, and SEQ ID NO: 104 is the fusion polypeptide comprising SEQ ID NOs: 85 and 91. See sequence alignments below.
Alignment of the ‘859 Patent’s SEQ ID NO: 85 and instant SEQ ID NO: 85:
Query Match 100.0%; Score 620; DB 1; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS 119
Alignment of the ‘859 Patent’s SEQ ID NO: 91 and instant SEQ ID NO: 91:
Query Match 100.0%; Score 1224; DB 1; Length 226;
Best Local Similarity 100.0%;
Matches 226; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 60
Qy 61 GVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 120
Qy 121 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 180
Qy 181 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 226
||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 226
Alignment of the ‘859 Patent’s SEQ ID NO: 136 and instant SEQ ID NO: 136:
Query Match 100.0%; Score 1844; DB 1; Length 346;
Best Local Similarity 100.0%;
Matches 345; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRELIYNQREGPFPRV 60
Qy 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TTVSDTTKRNNMDFSIRIGAITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSD 120
Qy 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 180
Qy 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG 240
Qy 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 300
Qy 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
|||||||||||||||||||||||||||||||||||||||||||||
Db 301 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 345
The claims in the ‘859 Patent differ from the instant invention by not reciting that the polypeptide only comprises an SIRP-α D1 variant of instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations and not reciting a method of treating urothelial cancer with a combination of the SIRP-α D1-Fc variant fusion polypeptide and enfortumab vedotin.
The teachings of Kauder et al., Pons et al, and Maas et al. are outlined in the 103 rejection above. It is noted that the ‘859 Patent’s SEQ ID NO: 104 is identical to Kauder et al.’s ALX148 and Pons et al.’s SEQ ID NOs: 104 and 136. See the 103 rejection above.
It would be obvious to one of ordinary skill in the art modify the ‘859 Patent to incorporate the teachings of Kauder et al. or Pons et al. and Maas et al. to specifically select a polypeptide that comprises an SIRP-α D1 variant of instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations and a method of treating urothelial cancer with a combination of the SIRP-α D1-Fc variant fusion polypeptide and enfortumab vedotin. This is because combination therapies of EV with immunotherapies and cytotoxic chemotherapies, such as Kauder et al.’s ALX148 or Pons et al.’s fusion polypeptide, are encouraging and provide an excellent treatment option for patients with UC (Maas et al.).
Bladder cancer, a type of UC, is very common and there is a high unmet need for new therapies (either alone or in combination with ICI or chemotherapy) to expand the first-line, the platinum-refractory, and the post-ICI space in mUC treatment (Maas et al.). This medical need could be addressed by EV given its encouraging ORR and favorable tolerability (Maas et al.).
ALX148, also known as Evorpacept, is a CD47-blocking molecule that was generated by fusing a modified SIRPα D1 domain (i.e. instant SEQ ID NO: 85) to an inactive human IgG1 Fc comprising L234A, L235A, G237A, and N297A mutations (Kauder et al). CD47 is a widely expressed cell surface protein that functions as an immune checkpoint in cancer (Kauder et al). ALX148 blocks the CD47-SIRPα interaction and induces antitumor immunity by bridging innate and adaptive immune responses while maintaining a favorable preclinical safety profile (Kauder et al).
Regarding Pons et al., high affinity SIRP-α constructs can effectively attenuate tumor growth and synergize with rituximab, an anti-CD20 antibody, in vivo (Pons et al.).
Given that bladder cancer, a type of UC, is so common (Maas et al.), combination therapies of EV with immunotherapies and cytotoxic chemotherapies are encouraging and provide an excellent treatment option for patients with UC (Maas et al.), ALX148, an ICI, enhances anti-tumor activity in combination with a variety of cancer therapies (Kauder et al.), and high affinity SIRP-α constructs can effectively attenuate tumor growth and synergize with anti-cancer antibodies in vivo (Pons et al.); it would be obvious to a skilled artisan, with the goal of improving the anti-cancer activity of EV for treating advanced or metastatic UC, to specifically select a polypeptide that comprises an SIRP-α D1 variant of instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations and include it in a method of treating urothelial cancer or to modify the ‘859 Patent’s method of treating cancer for a method of treating urothelial cancer, including bladder cancer, with a combination specifically of a polypeptide that comprising an SIRP-α D1 variant of instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations and enfortumab vedotin with a reasonable expectation of success.
Kauder et al. teach that ALX148 can be used in combination with a wide range of anti-cancer antibodies and Pons et al. teach that their SIRP-α D1-Fc variant fusion polypeptide is used in combination with an antibody, including an anti-cancer antibody, such as Maas et al.’s EV. ALX148 and Pons et al.’s SIRP-α D1-Fc variant fusion polypeptide, which are identical to the ‘859 Patent’s polypeptide comprising an SIRP-α D1 variant of instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations, would be expected to reduce any suppressed tumor cell phagocytosis or other innate or adaptive immune functions caused by the CD47-SIRPα signaling axis that may hinder EV treatment of UC.
It is also noted that regarding claims 12-18 drawn to the dosing of EV and the fusion polypeptide, determination of the optimal intervals of treatment and the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made and lends no patentable import to the claimed invention. The duration of treatment, the effective dosages and like factors are well within the knowledge and expertise of the medical practitioner.
It would be obvious to one of ordinary skill in the art at the time Applicants' invention was filed to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between Applicant’s claimed method and that suggested by the teachings of the prior art, the differences would be appear minor in nature. Although the prior art do not teach all the various permutations of interval ranges as claimed in claims 12-18, it would be conventional and within the skill of the art to identify the optional intervals of treatment. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP §§ 2144.05 part II A.
Regarding claim 26, while neither Kauder et al. or Pons et al. specifically teach treating a human, both references teach methods of treating mice comprising xenografts of human tumors. It is well known that mice comprising xenografts of human tumors are meant to model treatment in humans. Therefore, been it would have been obvious to a skilled artisan to use the combination therapy taught by the ‘859 Patent in view Kauder et al. or Pons et al. and Maas et al. in a human specifically.
Nonetheless, Maas et al. teach several clinical trials using EV to treat UC in humans thereby providing further rationale for a combination therapy of EV and the SIRP-α D1-Fc variant fusion polypeptide for treating UC in humans.
It is further noted that obtaining cDNA / nucleic acids from protein sequences has been routine and conventional in the art and used to make proteins of interest, including polypeptides of interest. For example, expression vectors can comprise polynucleotides sequences encoding amino acids, in turn polypeptides (e.g., polypeptides comprising instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations). Given that obtaining cDNA / nucleic acids from protein sequence sequences is routine and conventional, It would be obvious to the ordinary artisan to obtaining cDNA to produce proteins of interest.
This applies to the instant case where it would be obvious to a skilled artisan to obtain the isolated nucleic acid and the vector of the instant invention from the polypeptide constructs of the ‘859 Patent.
As such, the claims in the ‘859 Patent would render the instant claims obvious.
Claims 1-19, 21-23, 25, and 26 are (provisionally) rejected on the ground of nonstatutory double patenting (NSDP) as being unpatentable over the claims in the following U.S. Patents and Application in view of Kauder et al. 2018 (PLoS ONE. 13(8): e0201832. 1-33) as evidenced by post-filing art Evorpacept (GtoPdb Ligand ID: 11592, ALX148) (n.d.) IUPHAR Guide to Immunopharmacology (https://www.guidetoimmunopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=11592) or Pons et al. 2020 (U.S. Patent No. 10,696,730, an IDS reference filed 10/15/2024) and Maas et al. 2021 (Expert Opin. Biol. Ther. 21(7), 801-809) for similar reasons as the ‘859 Patent above.
The instant claims are drawn to a method of treating urothelial cancer in an individual, comprising administering to the individual (a) an effective amount of a fusion polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, and (b) an effective amount of enfortumab vedotin, wherein the SIRPα D1 domain variant of the fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 85; and wherein the Fc domain variant of the fusion polypeptide is (i) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat
Claims 1-28 of U.S. Patent No. 11,639,376 (the ‘376 Patent, an IDS reference filed 10/15/2024) are drawn to a polypeptide, comprising: (a) a signal-regulatory protein α (SIRP-α) polypeptide or a fragment thereof that is capable of binding CD47; and (b) an Fc variant, wherein the Fc variant is a human IgG1 Fc region comprising mutations L234A, L235A, G237A, and N297A; a method of treating an individual having a disease or disorder; a nucleic acid, a vector, a host cell, a method of producing a polypeptide; a pharmaceutical composition, and a dimer.
It is noted that SEQ ID NO: 85 of the ‘376 Patent is identical to instant SEQ ID NO: 85.
Claims 1-6, 9, 12, and 13 of U.S. Patent No. 12,527,838 (the ‘838 Patent) are drawn to a method of treating cancer in an individual, comprising administering to the individual an effective amount of: (a) a polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, (b) trastuzumab, (c) ramucirumab, and (d) paclitaxel; wherein the SIRPα D1 domain variant comprises the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 85; wherein the Fc domain variant is a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat; wherein the cancer is gastric cancer or gastroesophageal junction (GEJ) cancer, and wherein the individual has received at least one prior therapy for the gastric or the GEJ cancer.
It is noted that SEQ ID NOs: 85, 91, 136 are identical to instant SEQ ID NOs: 85, 91, 136.
Claims 10-13, 27, 28, 31, 32 and 59-63 of U.S. Application No. 19/084,515 (the ‘515 Application) are drawn to a method of treating HER2-positive cancer in an individual, comprising administering to the individual an effective amount of (a) a polypeptide comprising a SIRPaD1 domain variant and an Fc domain variant, and (b) an anti-HER2 antibody, wherein the SIRPaD1 domain variant comprises the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 85;wherein the Fc domain variant is (i) a human IgGI Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat;(ii) a human IgG2 Fc region comprising A330S, P331S, and N297A mutations, wherein numbering is according to the EU index of Kabat;(iii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, anddelG236 mutations, wherein numbering is according to the EU index of Kabat; or (iv) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, delG236, and N297A mutations, wherein numbering is according to the EU index of Kabat; and wherein the cancer in the individual has progressed following a prior treatment with a fluoropyrimidine-based therapy and/or a prior treatment with an anti-HER2 antibody, and wherein the individual is a human.
It is noted that SEQ ID NOs: 85, 91, 136 are identical to instant SEQ ID NOs: 85, 91, 136.
Claims 1-6 of U.S. Patent No. 12,098,214 (the ‘214 Patent) are drawn to a method of treating cancer in an individual, comprising administering to the individual an effective amount of: (a) a polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, (b) an anti-HER2 antibody, (c) an anti-VEGFR2 antibody, and (d) paclitaxel; wherein the SIRPα D1 domain variant comprises the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 85; wherein the Fc domain variant is a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat; wherein the cancer is gastric cancer (GC) or gastroesophageal junction (GEJ) cancer, wherein the individual has received at least one prior therapy for the gastric or the GEJ cancer; and wherein the polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant is administered at a dose of 30 mg/kg once every two weeks, wherein the anti-HER2 antibody is trastuzumab and is administered at an initial dose of 6 mg/kg followed by 4 mg/kg once every two weeks, wherein the anti-VEGFR2 antibody is ramucirumab and is administered at a dose of 8 mg/kg once every two weeks, and wherein the paclitaxel is administered at a dose of 80 mg/m2 on Days 1, 8, and 15 of every 28-day cycle.
It is noted that SEQ ID NO: 85 is identical to instant SEQ ID NO: 85.
Claims 1-17 of U.S. Patent No. 12,343,377 (the ‘377 Patent) are drawn to a method of treating a myeloid cancer in an individual having a myeloid cancer, comprising administering to the individual an effective amount of: (a) a fusion polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, and (b) azacitidine; wherein the SIRPα D1 domain variant of the fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 85; wherein the Fc domain variant of the fusion polypeptide is (i) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat; (ii) a human IgG2 Fc region comprising A330S, P331S, and N297A mutations, wherein numbering is according to the EU index of Kabat; (iii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, and delG236 mutations, wherein numbering is according to the EU index of Kabat; or (iv) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, delG236, and N297A mutations, wherein numbering is according to the EU index of Kabat; and wherein the C-terminus of the SIRPα D1 domain variant of the fusion polypeptide is linked to the N-terminus of the Fc-domain variant.
It is noted that SEQ ID NOs: 85, 91, 136 are identical to instant SEQ ID NOs: 85, 91, 136.
The claims in the above Patents and Application differ from the instant invention by not reciting that the polypeptide only comprises an SIRP-α D1 variant of instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations; a method of treating urothelial cancer; or a combination with enfortumab vedotin (EV).
The teachings of Kauder et al., Pons et al, and Maas et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art modify the above Patents and Application to incorporate the teachings of Kauder et al. or Pons et al. and Maas et al. to specifically select a polypeptide that comprises an SIRP-α D1 variant of instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations and to include a method of treating urothelial cancer with a combination of the SIRP-α D1-Fc variant fusion polypeptide and enfortumab vedotin. This is because combination therapies of EV with immunotherapies and cytotoxic chemotherapies, such as Kauder et al.’s ALX148 or Pons et al.’s fusion polypeptide, are encouraging and provide an excellent treatment option for patients with UC (Maas et al.).
Bladder cancer, a type of UC, is very common and there is a high unmet need for new therapies (either alone or in combination with ICI or chemotherapy) to expand the first-line, the platinum-refractory, and the post-ICI space in mUC treatment (Maas et al.). This medical need could be addressed by EV given its encouraging ORR and favorable tolerability (Maas et al.).
ALX148, also known as Evorpacept, is a CD47-blocking molecule that was generated by fusing a modified SIRPα D1 domain (i.e. instant SEQ ID NO: 85) to an inactive human IgG1 Fc comprising L234A, L235A, G237A, and N297A mutations (Kauder et al). CD47 is a widely expressed cell surface protein that functions as an immune checkpoint in cancer (Kauder et al). ALX148 blocks the CD47-SIRPα interaction and induces antitumor immunity by bridging innate and adaptive immune responses while maintaining a favorable preclinical safety profile (Kauder et al).
Regarding Pons et al., high affinity SIRP-α constructs can effectively attenuate tumor growth and synergize with rituximab, an anti-CD20 antibody, in vivo (Pons et al.).
Given that bladder cancer, a type of UC, is so common (Maas et al.), combination therapies of EV with immunotherapies and cytotoxic chemotherapies are encouraging and provide an excellent treatment option for patients with UC (Maas et al.), ALX148, an ICI, enhances anti-tumor activity in combination with a variety of cancer therapies (Kauder et al.), and high affinity SIRP-α constructs can effectively attenuate tumor growth and synergize with anti-cancer antibodies in vivo (Pons et al.); it would be obvious to a skilled artisan, with the goal of treating bladder cancer and improving the anti-cancer activity of EV, to specifically select a polypeptide that comprises an SIRP-α D1 variant of instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations and include it in a method of treating urothelial cancer or to modify the above Patents and Application method of treating cancer for a method of treating urothelial cancer, including bladder cancer, with a combination specifically of a polypeptide that comprising an SIRP-α D1 variant of instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations and enfortumab vedotin with a reasonable expectation of success.
Kauder et al. teach that ALX148 can be used in combination with a wide range of anti-cancer antibodies and Pons et al. teach that their SIRP-α D1-Fc variant fusion polypeptide is used in combination with an antibody, including an anti-cancer antibody, such as Maas et al.’s EV. ALX148 and Pons et al.’s SIRP-α D1-Fc variant fusion polypeptide, which are identical to the above Patents and Applications’ polypeptide comprising an SIRP-α D1 variant of instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations, would be expected to reduce any suppressed tumor cell phagocytosis or other innate or adaptive immune functions caused by the CD47-SIRPα signaling axis that may hinder EV treatment of UC.
It is also noted that regarding claims 12-18 drawn to the dosing of EV and the fusion polypeptide, determination of the optimal intervals of treatment and the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made and lends no patentable import to the claimed invention. The duration of treatment, the effective dosages and like factors are well within the knowledge and expertise of the medical practitioner.
It would be obvious to one of ordinary skill in the art at the time Applicants' invention was filed to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between Applicant’s claimed method and that suggested by the teachings of the prior art, the differences would be appear minor in nature. Although the prior art do not teach all the various permutations of interval ranges as claimed in claims 12-18, it would be conventional and within the skill of the art to identify the optional intervals of treatment. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP §§ 2144.05 part II A.
Regarding claim 26, while neither Kauder et al. or Pons et al. specifically teach treating a human, both references teach methods of treating mice comprising xenografts of human tumors. It is well known that mice comprising xenografts of human tumors are meant to model treatment in humans. Therefore, been it would have been obvious to a skilled artisan to use the combination therapy taught by above Patents and Applications in view Kauder et al. or Pons et al. and Maas et al. in a human specifically.
Nonetheless, Maas et al. teach several clinical trials using EV to treat UC in humans thereby providing further rationale for a combination therapy of EV and the SIRP-α D1-Fc variant fusion polypeptide for treating UC in humans.
It is further noted that obtaining cDNA / nucleic acids from protein sequences has been routine and conventional in the art and used to make proteins of interest, including polypeptides of interest. For example, expression vectors can comprise polynucleotides sequences encoding amino acids, in turn polypeptides (e.g., polypeptides comprising instant SEQ ID NO: 85 and a human IgG1 Fc variant region comprising L234A, L235A, G237A, and N297A mutations). Given that obtaining cDNA / nucleic acids from protein sequence sequences is routine and conventional, It would be obvious to the ordinary artisan to obtaining cDNA to produce proteins of interest.
This applies to the instant case where it would be obvious to a skilled artisan to obtain the isolated nucleic acid and the vector of the instant invention from the polypeptide constructs of the above Patents and Applications.
As such, the claims in the above Patents and Applications would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection for the co-pending Patent Applications since the claims are in fact not patented (U.S. Application 19/084,515).
Conclusion
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641